Lamivudine (alternatively referred to herein as LMV, and often typically referred to in the art as 3TC) is an antiviral drug that is presently marketed as EPIVIR (GlaxoSmithKline) for the treatment of HIV, HBV and HTLV. Chemically lamivudine is (−)-cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl-(1H)-pyrimidin-2-one and has the following structure:

WO 91/017159 A1 discloses the preparation of lamivudine as a white powder using enzyme-mediated enantioselective catabolism of a mixture of lamivudine and its enantiomer (see Examples 4 and 5).
U.S. Pat. No. 5,905,082 discloses that LMV exhibits polymorphism and can exist as needle-shaped crystals (referred to as Form I) and bipyramidal crystals (referred to as Form II). Form I is disclosed to be less stable than Form II as certain operations such as milling are said to cause conversion of Form I to Form II. The two polymorphic forms are characterized and distinguished by their melting behavior, infrared spectra, and DSC scans. The reference discloses that Form I can be obtained by crystallization from aqueous solution or by azeotropic distillation with 1-propanol, and that Form II can be obtained by recrystallization of LMV from non-aqueous media, in particular a C2-6 alcohol, industrial methylated spirit (IMS; denatured ethanol) or 1-propanol. The reference also reports that Form II can be obtained by heating Form I above its melting point and allowing the melt to cool or, alternatively, by grinding or milling Form I. Example 1 in US '082 discloses the preparation of Form I by heating a suspension of LMV (referred to as “Intermediate 5” in the example) in water to 45° C. to obtain a solution, and then cooling the solution to 30° C. to provide an unstirrable crystalline mass which was broken up into a suspension that was stirred at ca. 10° C. for 1 hour. The product was then filtered, washed twice with IMS, and dried in vacuo at 45° C. for 24 hours to provide fine needle crystals (Form I). Example 2 discloses the preparation of Form II by refluxing a suspension of Form I in IMS to provide a solution, filtering the hot solution, distilling the filtrate, seeding the distilled filtrate, and cooling from 80° C. to 25° C. over 1 hour. The product isolated therefrom was aggregates of bipyramids (Form II). Example 3 discloses the formation of 100% Form II from Form I by heating a suspension of Form I from Example 1 in IMS with stirring at 50° C. for a total of about 25 hours, then cooling to 20° C. and stirring the suspension for 1 hour, and then isolating Form II therefrom.
Jozwiakowski et al., J. Pharm. Sci. 1996, 85 (2), pp. 193-199 discloses the preparation of Form I by dissolving LMV in hot water, adding an equal volume of MeOH, and cooling in a refrigerator. Form I and Form II were characterized by SEM, polarized light microscopy, TGA, DSC, and XRPD. The reference describes Form I as an 0.2 hydrate and Form II as an anhydrate. The reference also describes the solubility behavior of Forms I and II in various recrystallization solvents (i.e., water, MeOH, EtOH, n-PrOH, 2-PrOH, n-BuOH, sec-BuOH, EtOAc, acetone, and acetonitrile) at 5° C., 15° C., 25° C., 35° C. and 45° C. The solubility behavior of the crystalline forms in EtOH-water mixtures at 25° C. was also investigated, and it was disclosed that >18-20% water must be present in EtOH to convert the excess solid to Form I at equilibrium.
Harris et al., J. Chem. Soc., Perkin Trans. 2 1997, 2653-2659 provides a further study characterizing and comparing Forms I and II. It is disclosed that Form I was crystallized as needles from solutions in water, methanol, or aqueous alcohols and that Form II was obtained as bipyramids on slow recrystallization from dry EtOH, n-PrOH, or mixtures of EtOH with less polar organic solvents. The two forms were characterized by DSC, 13C and 1H NMR, IR and XRPD. Among its findings was that Form II has a highly symmetrical lattice and Form I has an asymmetric unit containing 5 non-equivalent molecules and one water molecule for every 5 of LMV (i.e., 0.2 mol hydrate).
WO 03/027106 A1 discloses a process for the preparation of Form II in which LMV salicylate is suspended in a solvent selected from aliphatic ketones, esters, and C1-8 straight or branched-chain ethers, refluxing the suspension at the reflux temperature of the solvent, adding organic base at the reflux temperature, and then cooling the mixture and filtering to obtain Form II. The process is illustrated in Example 1 (solvent=EtOAc, base=TEA) and Example 2 (solvent=acetonitrile, base=TEA).
WO 2007/119248 A1 discloses a crystalline hemihydrate of lamivudine which is referred to therein as Form III. The reference provides a method for preparing Form III by dissolving LMV in water at 45° C., cooling the resulting solution to 30° C., optionally seeding with Form III crystals, further cooling to 10° C. at a range of 0.5° C./minute to 3.5° C./minute, and then isolating the crystals by filtration optionally washing with alcohol and drying at 45-55° C. Examples 14 and 15 respectively describe the preparation of Form I and Form. II using substantially the same procedures as set forth in Examples 1 and 2 respectively in U.S. Pat. No. 5,905,082.
WO 2008/114279 A2 discloses the preparation and characterization of an amorphous form of LMV, a crystalline solvate of LMV and dimethylacetamide (referred to therein as Form III), a crystalline solvate of LMV and 1-methyl-2-pyrrolidinone (referred to therein as Form IV), and a crystalline anhydrous polymorph of LMV referred to therein as Form V. The Form III reported in this reference (a DMAC solvate) and the Form III reported in WO 2007/119248 discussed above (crystalline hemihydrate) are not the same form of LMV. The term “Form III” as used herein refers to the crystalline hemihydrate.
WO 2008/114279 discloses that the amorphous form of LMV can be prepared by heating Form V to form a melt and then cooling the melt and that Form I can be obtained from the amorphous form. It is disclosed that Form I can be prepared by storing the amorphous LMV form at a relative humidity of >90% for several days (see Example 28), and can also be prepared by heating the amorphous LMV form at about 40° C. for several days (see Example 29). The reference also includes several examples disclosing the preparation of Form I by processes that involve cooling a hot solution of LMV in organic solvent(s) to ambient temperature. The reference also discloses examples of the preparation of Form I by the fast evaporation of a solution of LMV in organic solvent on a watch glass, and by stirring a suspension of the amorphous LMV in organic solvent at ambient temperature overnight.
WO 2009/037538 A2 discloses three processes for the preparation of Form I. The first process involves dissolving LMV in an aqueous alcohol (e.g., 15-20% aqueous EtOH at 35-60° C., preferably 45-55° C.); filtering the solution through celite; removing the alcohol under reduced pressure below 42° C.; precipitating the product from the residue by addition of EtOAc or methyl isobutyl ketone; and filtering and drying the wet material (e.g., at 40-50° C.) under reduced pressure until the water content is ≦1.8% w/w. The first process is exemplified by Examples 1 (aqueous EtOH; EtOAc), 3 (aqueous MeOH; EtOAc) and 4 (aqueous EtOH; methyl isobutyl ketone). The second process comprises treating LMV salicylate monohydrate with an organic base in an organic solvent and isolating Form I. The second process is exemplified in Examples 2 (temperature=25-30° C.; base=TEA; solvent=EtOAc) and 5 (temperature=25-30° C.; base=TEA; solvent=methyl isobutyl ketone). The third process involves slurrying LMV in a mixture of EtOAc and water and isolating Form I therefrom. The third process is illustrated in Example 6, wherein a mixture of Form I and Form II was slurried in a mixture of EtOAc (210 mL) and water (5 mL) containing TEA (0.2 g) at 20-30° C.; the slurry was stirred overnight at 20-30° C.; and the product was filtered, washed with EtOAc, and dried under reduced pressure at 40-45° C. to provide Form I.
WO 2009/069013 A1 discloses the preparation of Form I by a process which comprises dissolving LMV in water at 38-45° C. to obtain a solution, cooling the solution to a temperature of ≦30° C. in ≦10 minutes to obtain a mixture, stirring the mixture at a temperature ≦30° C. and isolating the solid therefrom, and then washing the solid with water to obtain Form I. The Form I product obtained by this process is said in the reference to be stable; i.e., the reference purports that Form I obtained by the process will not convert to Form II when subjected to milling or when stored at up to 45° C. at a relative humidity of 25% to 85%.
WO 2009/127996 A1 discloses another crystalline form of lamivudine referred to therein as Form IV. It is disclosed that Form IV can be prepared by dissolving LMV in methanol to provide a solution, cooling the resulting solution to ≦15° C. to obtain a mixture, and isolating Form IV from the mixture.
Variankaval et al., Organic Process R&D 2007, 11, pp. 229-236 discloses a study of the water activity-mediated control of crystalline phases of N-cyclopropyl-1-[3-[(1-oxidopyridin-3-yl)ethynyl]phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide. Water activities in solvent-water mixtures were calculated using the NRTL-RK model as implemented on ASPEN Properties software. The document concluded (p. 236) that the “the critical parameter in designing suitable crystallization processes in systems characterized by both anhydrous and hydrated forms is the activity of water rather than concentration in the aqueous solution.” (emphasis in original)